The long-term objectives of this research are the elucidation of the mechanism controlling the synthesis of hemoglobin, especially the role of heme and of protein synthesis in regulating the synthesis of globin and other proteins in normal and abnormal erythroid cells, and the definition of the role of heme in the differentiation and maturation of erythroid and other eukaryotic cells. The specific aims include elucidation of the mechanisms of regulation of initiation of protein synthesis by phosphorylation and dephosphorylation, with emphasis on the heme-regulated elf-2 alpha protein kinase; the interaction of eIf-2 and the reversing factor, RF, and the role of RF in the recycling of eIF-2 the relationship between the molecular structure of the heme-regulated eIF-2 alpha kinase and its activation and activity, and the distribution and function of the same and similar kinases in erythroid and non-arythroid cells. This research is relevant not only to the regulation of protein synthesis generally in eukaryotic cells but specifically is significant for understanding human anemias characterized by heme deficiency, i.e., iron-lack anemia, one of the world's most prevalent disorders, lead poisoning, and the sideroblastic anemias. The methodology involves in situ and vitro studies of the components involved in initiation of protein synthesis, and the purification of the heme-regulated eIF-2 alpha kinase and analysis of its structure.